Illumination for photodynamic therapy

ABSTRACT

An illumination system (1) for photodynamic therapy is provided, the illumination system comprising an illumination source (2), which is configured to emit an electromagnetic radiation (3) to illuminate a target surface (4) during operation, and an electronic control unit (5), wherein the illumination source is configured such that the intensity of the electromagnetic radiation emitted by the illumination source can be varied, wherein the electronic control unit is operatively connected to the illumination source and configured to control operation of the illumination source according to an illumination protocol during an illumination session performed with the illumination system, and wherein the illumination protocol comprises instructions to operate the illumination source during the illumination session in a plurality of different modes, the modes comprising: a) a first mode, wherein, in the first mode, the electronic control unit controls operation of the illumination source such that the intensity of the electromagnetic radiation emitted by the illumination source is increased continuously or quasi-continuously from a base intensity B to a target intensity T within a first mode time interval, b) a second mode, wherein, in the second mode, the electronic control unit controls operation of the illumination source such that the intensity of the electromagnetic radiation emitted by the illumination source is constant or substantially constant for a second mode time interval, and c) a third mode, wherein, in the third mode, the electronic control unit controls operation of the illumination source such that the illumination source is operated such that darker phases and illumination phases alternate for a third mode time interval, wherein the intensity of the electromagnetic radiation emitted by the illumination source is lower in the darker phases than in the illumination phases, or wherein, in the darker phases the illumination source does not emit electromagnetic radiation whereas the illumination source emits electromagnetic radiation in the illumination phases. Furthermore, a computer program product and a kit for treating a disease are provided and a method for operating an illumination source and a method for treating a skin disease.

This disclosure relates to an illumination system for photodynamictherapy, the illumination system comprising an illumination source,which is configured to emit an electromagnetic radiation to illuminate atarget surface during operation, and an electronic control unit.

The disclosure also relates to a method for operating an illuminationsource, a computer program product, such as a data carrier, a kit fortreating a disease and a method for treating a skin disease.

Photodynamic therapy (PDT) has been widely studied and severalapproaches have been used successfully for treatment. In general thereare three requirements for PDT: a photosensitizer, molecular oxygen andlight of a specific wavelength. For dermatological PDT usually aprodrug, for example aminolevulinic acid (ALA), is topically applied tothe skin. Subsequently, the prodrug is then converted by the cells, e.g.by neoplastic cells, into the actual photosensitizer. The molecularmechanism of action in PDT is based on cellular ALA uptake, synthesisand accumulation of the photosensitizer, which can be excited by lightof specific wavelengths leading to the formation of reactive oxygenspecies (ROS), upon the presence of oxygen. The ROS can initiate celldeath, e.g. in the form of apoptosis, necrosis and autophagy.

However, one of the major issues that hinder broad acceptance of PDT bypatients is the relatively high amount of pain perceived by the patientsduring the illumination which ranges from mild inconvenience to severepain to a point where the treatment has to be aborted. In addition,although PDT is a highly effective treatment method, reoccurrence ofsome diseases like actinic keratosis is common and thus patients often,although having been successfully treated, later develop differentlesions at different skin areas and again require medical intervention.Moreover, some patients are not completely cured after a single PDTsession and require a second session. If the first PDT they received wasvery painful the chances of beginning or completing a second PDT aresmall despite the fact that it offers supreme efficacy compared to othertherapy options. As a result, the acceptance of many patients to undergotreatment or re-treatment decreases. This of course has great negativeimplications for an individual PDT and PDT as a whole.

Consequently, pain reduction is of crucial interest to increaseacceptance levels of PDT treatment as a whole, thus increasing the useof this superior treatment.

Nevertheless, PDT efficacy is also limited by any of the involvedfactors, i.e. photosensitizer, oxygen, and light. Reduced availabilityof any of these factors may hamper with ROS formation. Optimizedpharmaceutical forms, pretreatments and incubation modalities can ensureproper and abundant deposition of the photosensitizer. Still, light hasto reach a molecule in sufficient quantities and oxygen needs to bepresent as an energy acceptor.

In particular the light of the illumination at the appropriatewavelength to activate the respective photosensitizer needs to be madeavailable at a sufficient dose. For topical applications, a frequentlyused photosensitizer is protoporphyrin IX (PpIX), mostly produced inskin cells by application of a precursor molecule, such as ALA. PpIX canbe activated by light of a variety of different wavelengths of which red(approx. 635 nm), blue (approx. 420 nm), yellow (approx. 542 nm) orgreen (approx. 506 nm) light are most frequently used. Generally, alight dose received by a target, e.g. the treated skin, depends on threemain factors. The irradiance provided by the light source, the distancebetween the target area and the light source, and the duration of theillumination.

The current practice is to apply the entire light dose within a shortinterval (e.g. ranging from 7 to 12 minutes with red light or 15-20minutes with blue light). Usually, this approach is limited by theoccurrence of pain. Moreover, photobleaching of the photosensitizer mayoccur to a greater extent at higher light intensities and may limit thetreatment efficiency. Photobleaching describes the effect that thephotosensitizer is inactivated by permanent disruption of its chemicalstructure, e.g. by cleavage of covalent bonds. This photobleachingeffect may coincide with temporal oxygen depletion in the target tissuedue to a massive initial reaction. This leads to a rapid decrease inoxygen, which is required for ROS formation. All photobleaching thatoccurs during the phase where oxygen is limited is likely to beunproductive, as it yields fewer cytotoxic singlet oxygen.

It should be noted that the statements above should not be construed asbeing admitted prior art. They are only made to illustrate thebackground of the presently disclosed concepts and may not have beenmade available to the public yet.

It is an object of the invention to provide an improved illuminationsystem for photodynamic therapy, an improved method for operating anillumination source, an improved computer program product, such as adata carrier, an improved kit for treating a disease, and/or an improvedmethod for treating a skin disease, which preferably allow or areconfigured to limit the pain burden, expediently while maintaining anacceptable effectiveness of the therapy, and/or which allow or areconfigured to increase the effectiveness of the therapy.

The respective object may, inter alia, be achieved by the subject matterof the independent claims. Advantageous embodiments and refinements arethe subject matter of the dependent claims. However, furtheradvantageous concepts may be disclosed herein besides the ones which arecurrently claimed.

One aspect of the present disclosure relates to an illumination systemfor photodynamic therapy, wherein the illumination system comprises anillumination source, which is configured to emit an electromagneticradiation to illuminate a target surface during operation, and anelectronic control unit. The illumination source is configured such thatthe intensity of the electromagnetic radiation emitted by theillumination source can be varied, wherein the electronic control unitis operatively connected to the illumination source and configured tocontrol operation of the illumination source according to anillumination protocol during an illumination session performed with theillumination system, and wherein the illumination protocol comprisesinstructions to operate the illumination source during the illuminationsession in a plurality of different modes, the modes comprising:

a) a first mode, wherein, in the first mode, the electronic control unitcontrols operation of the illumination source such that the intensity ofthe electromagnetic radiation emitted by the illumination source isincreased continuously or quasi-continuously from a base intensity B toa target intensity or a targeted intensity T within a first mode timeinterval,b) a second mode, wherein, in the second mode, the electronic controlunit controls operation of the illumination source such that theintensity of the electromagnetic radiation emitted by the illuminationsource is constant or substantially constant for a second mode timeinterval, and/orc) a third mode, wherein, in the third mode, the electronic control unitcontrols operation of the illumination source such that the illuminationsource is operated such that darker phases and illumination phasesalternate for a third mode time interval, wherein the intensity of theelectromagnetic radiation emitted by the illumination source is lower inthe darker phases than in the illumination phases, or wherein, in thedarker phases the illumination source does not emit electromagneticradiation whereas the illumination source emits electromagneticradiation in the illumination phases. The control unit may be configuredto control the operation voltage and/or the operation current providedto the illumination source in a manner which results in operation of theillumination source as desired for the respective mode.

The proposed illumination system may limit or reduce the perceived painburden. This is achieved, inter alia, by operating the illuminationsource during the illumination session in the above-mentioned differentmodes as will be explained in more detail below. The proposedillumination system and particularly the illumination protocol mayincrease the effectiveness of the PDT. Thus, the proposed system and/orthe protocol may provide for a pain optimized yet still efficienttherapy.

In the first mode the intensity of the electromagnetic radiation emittedby the illumination source is increased continuously orquasi-continuously from a base intensity B to a target intensity T. Theterm “quasi-continuously” may mean that the intensity of the emittedradiation is constant for a maximum duration less than or equal to oneof the following values: 5 s, 4 s, 3 s, 2 s, is or 500 ms. The term“continuously” may mean that the intensity of the emitted radiation isconstant for a maximum duration less than the values associated with“quasi-continuously”, preferably less than or equal to one of thefollowing values: 400 ms, 300 ms, 200 ms, 100 ms, 50 ms, 25 ms, 20 ms,15 ms, 10 ms, 5 ms, 4 ms, 3 ms, 2 ms, 1 ms. As the emitted intensity ischaracterized or determined by the electrical energy provided to theillumination source, according values may be characteristic for theoperation voltage and/or current being increased continuously orquasi-continuously.

The continuous or quasi-continuous increase in intensity may lead to amoderate reaction onset. The increase in intensity may reduce initialphotobleaching and/or promote re-oxygenation of the treated skin. Apartfrom that, the continuous increase of the irradiance may trigger asufficient photodynamic effect, including initial inflammatory reactionsthat induce vasodilation for even better oxygen supply, wherein thephotodynamic effect describes the process during PDT which leads to thedestruction of cells. Therefore, the efficiency of the treatment duringthe first mode may be ensured.

Another advantage of the first mode is that the continuous increase ofthe irradiance on the skin—the irradiance on or of the skin depends onthe emitted intensity as well as on the distance between theillumination source and the skin—allows adaptation of the sensory nerveendings in the skin to the stimulus, which balances pain sensation andultimately leads to a reduced pain burden in patients. A slow increaseof the irradiance over an interval of between 4 to 10 minutes has provento be acceptable.

In the second mode the intensity of the electromagnetic radiationemitted by the illumination source is constant or substantiallyconstant. The term “substantially constant” may mean a maximum deviationfrom an intensity I of less than or equal to one of the followingvalues: 15%, 10%, 5%. I is the constant intensity during the secondmode. I may be equal to T.

The constant or substantially constant intensity of the electromagneticradiation in the second mode may provide comparatively high irradiance,preferably in a short time span. It may assist in or be responsible forsustaining a lasting photodynamic effect, preferably without causingunbearable pain burden, e.g. due to its limited duration.

In the third mode the illumination source is operated such that darkerphases and illumination phases alternate. The darker phases may allowthe neuronal activation to wear off to some extent, which leads to alower pain burden. The illumination phases may allow to achieve atargeted light dose for the illumination session. In the illuminationphases, the intensity is expediently greater than in the darker phases.In the darker phases, the illumination source may be operated to emit alower intensity or not emit radiation at all.

Moreover another advantage of the third mode may be the balanced rate ofoxygen consumption and oxygen resupply. The resupply of oxygen in thedarker phases may expediently support the efficiency of the treatment bypreventing late oxygen depletion.

Therefore, a combination of the first, second and third modes may leadto

-   -   a moderate reaction onset, to reduce the pain burden and to        reduce initial photobleaching and promote re-oxygenation of the        treated tissue,    -   a sufficient photodynamic effect, including initial inflammatory        reactions that induce vasodilation for even better oxygen        supply,    -   re-oxygenation and thus additional photosensitizer activation,        especially in the later phases of the illumination, e.g. when        higher or high fluence rates are used, in order to prevent late        oxygen depletion, and    -   a therapy duration which is increased only moderately or not at        all for achieving a given light dose on the irradiated target        while maintaining an effective light dose without creating an        unbearable pain burden.

In an embodiment B may be less than or equal to one of the followingvalues: 0.5 T, 0.45 T, 0.4 T, 0.35 T, 0.3 T. Alternatively oradditionally, B may be greater than or equal to one of the followingvalues: 0.1 T, 0.15 T, 0.2 T, 0.25 T, 0.3 T. Thus, B may be between 0.1T and 0.5 T or any other range formed by combining values of the twolistings.

Choosing B accordingly may allow for a sufficient adaptation of thesensory nerve endings in the skin to the stimulus, which may balancepain sensation. This may lead to a reduced pain burden. In addition, asufficient photodynamic effect may be achieved or triggered. Highervalues of B, e.g. greater than 0.6 T may cause too much initial painduring the illumination session. Values below 0.1 T may be insufficientto trigger a substantial photodynamic effect and/or lead to instableillumination due to technical restrictions.

In an embodiment the constant or quasi-constant intensity during thesecond mode may be the target intensity T in the first mode. This mayallow a direct transition from the first mode to the second mode. It isadvantageous that the efficiency of the treatment is not jeopardized byvarying the intensity once the target intensity has been reached. Inaddition, a direct transition from the first to the second mode leads toless irritation of the nerves of the patient and thus may also lead to alower pain burden.

In an embodiment the intensity during the illumination phases may be T.This may result in a reduced pain burden because the nerves may havebeen already adapted to T, e.g. from the preceding mode(s) of theillumination protocol.

In an embodiment the maximum intensity during the first mode, the secondmode, and the third mode may be T. This, likewise, may lead to lessirritation of the nerves of the patient and thus also contribute to alower pain burden.

In an embodiment the intensity may be increased in the first modelinearly from B to T. A linear increase may cause that the patient feelscomfortable as he can easily adjust to the rate of pain increase and theincrease may be more predictable.

In an embodiment the intensity may be increased in the first modestrictly monotonously. Stepwise increases in intensity are much morenoticeable to the patient than a strictly monotonous increase inintensity. Consequently, a strictly monotonous increase of intensityleads to less pain.

In an embodiment the intensity may be increased non-linearly in thefirst mode. At the beginning or the start of the first mode theintensity may be increased at a slower rate than later on in the firstmode. This may cause the beneficial effects of the photodynamic effectto appear earlier, wherein an initial phase for adaptation of the nervesand the intensity is retained.

In an embodiment, the illumination protocol comprises a priming mode.The priming mode may be a mode of operation of the illumination sourcewhich precedes the first mode. In the priming mode of operation, theintensity of the electromagnetic radiation emitted by the illuminationsource may be constant or substantially constant for a priming mode timeinterval. The intensity in the priming mode may be P. P may be less thanor equal to B, i.e. the base intensity in the first mode. Thesubject/patient irradiated using the protocol can become accustomed tothe irradiance during an initial operation of the illumination source inthe priming mode. When the priming mode is applied, the intensity in thefirst mode subsequent to the priming mode may be increased linearlyand/or with a higher rate than without the priming mode, preferablywithout significantly raising the perceived pain for the user.

In an embodiment the illumination source may be operated in the firstmode before it is operated in the second mode and/or before it isoperated in the third mode during the illumination session. The firstmode may be to adapt the nerves to the radiation intensity or the painburden during the illumination session. For this purpose, the first modepreferably initially uses a low intensity. In order to reduce thesensation of pain, it may therefore be advantageous to perform the firstmode before further modes, e.g. modes which may feature a higherintensity than the initial light intensity, e.g. B, of the first mode.

In an embodiment the illumination source may be operated in the secondmode after the first mode and/or before the third mode during theillumination session. Since the second mode may have a constantintensity, it is advantageous for reducing pain when the second mode ispreceded by the first mode, which may serve to adapt the nerves to thelight intensity of the second mode. Moreover, it is also expedient tohave the mode with the constant intensity (second mode) between theincreasing intensity (first mode) and the alternating illumination anddarker phases (third mode), as the second mode may be the one where thepain burden is highest. The following darker and illumination phases mayrender the higher pain in the intermediate portion of the illuminationsession less significant for the user. The user may preferably rememberthe moderate pain during the third mode and the low initial pain.

In an embodiment the beginning of the operation of the illuminationsource in the first mode may define the start of the illuminationsession and the end of the operation of the illumination source in thethird mode may define the end of the illumination session. If thepriming mode is applied, the beginning of the operation of theillumination source in the priming mode may define the beginning of theillumination session.

In an embodiment every mode selected from the first mode, the secondmode, and the third mode of operation of the illumination source mayoccur once, preferably only once, during the illumination session. Thus,the overall duration may be kept below 16 minutes, which is consideredacceptable by most patients and physicians, e.g. in terms of pain burdenand time consumption. This duration may include or exclude the operationin the priming mode.

In an embodiment the illumination system may have a target location ormay define a target location in which the target surface is to bearranged relative to the illumination source during the illuminationsession. The target location (i.e. the position of the target surfacerelative to the illumination source) may be defined by a bearingsurface, which is contacted by a section of the user's head, e.g. by theforehead or the chin. The section of the user's head may stay in contactwith the bearing surface during the entire session. The target locationmay be arranged at a distance from a radiation exit surface of theillumination source. A gaseous medium may be present between theradiation exit surface of the illumination source, e.g. a surface of anoptical element, e.g. a diffusor or a lens, and the target surfaceand/or the target location.

The term “target surface” as used herein may refer to a surface that isto be illuminated by the electromagnetic radiation emitted by theillumination source.

The term “target location” as used herein may refer to the position ofthe target surface relative to the illumination source. In other words,the target location may be a location which is determined by the designof the illumination device. The target location may be the position inwhich the surface which is to be illuminated should be arranged relativeto the illumination device during operation of the device, i.e. duringthe illumination session. For example, in the target location, theradiation generated by the illumination device may have a desiredirradiance distribution, e.g. along the target surface. If the targetsurface were arranged in a different location relative to theillumination source the irradiance distribution may be different and/ormay not be suitable for the desired purpose.

The term “bearing surface” as used herein may refer to a surface that issuitable to support a user's body part, such as the head, during anoperation, preferably in the target location. The body part may comprisethe target surface which should be illuminated using the illuminationdevice. The bearing surface may be formed by a mechanical support.

In an embodiment the distance between the radiation exit surface of theillumination source and the target location may be less than or equal toone of the following values: 20 cm, 15 cm 10 cm, 8 cm, 7 cm, 6 cm, 5 cm.Alternatively or additionally, the distance between the radiation exitsurface of the illumination source and the target location may begreater than or equal to one of the following values: 1 cm, 2 cm, 3 cm,4 cm, 5 cm. The distance between the radiation exit surface of theillumination source and the target location may be between 1 cm and 20cm, preferably between 5 cm and 8 cm.

PDT efficacy is potentially limited by any of the involved factors, i.e.photosensitizer, oxygen, and light dose. Generally, the light dosereceived by a target, e.g. the treated skin, depends on three mainfactors. One of it is the distance between the target surface and thelight source. The distance has a direct influence on the light dosereceived by a target, as the intensity at a specific location depends onthe distance of that location from the illumination source. A distancebetween 1 cm and 20 cm, preferably between 5 cm and 8 cm, isadvantageous because it can optimally unfold the effect of PDT.Furthermore, the perceived pain may be acceptable for patients in thedistances specified above, especially for the typically appliedirradiances.

In an embodiment the illumination source may comprise at least oneoptoelectronic semiconductor chip for generating the electromagneticradiation, e.g. a light-emitting diode chip. This allows a reliable,cost effective and accurate implementation of the illumination source.Optoelectronic chips allow tuning the emission wavelength easily to arequired (peak) wavelength, e.g. by appropriately engineering the activeregion of the chip, e.g. by band-gap engineering. Thus, electricalenergy may be efficiently converted into radiation energy in therelevant wavelength range.

In an embodiment the radiation emitted by the illumination source may beincoherent radiation. As compared to coherent radiation, incoherentradiation is easier to handle.

In an embodiment the radiation emitted by the illumination source may bemonochromatic, e.g. of light of one specific color.

In an embodiment the electromagnetic radiation may have a peakwavelength in the visible spectral range, e.g. in the red, blue, green,or yellow spectral range.

In an embodiment the electromagnetic radiation has a peak wavelength inthe red spectral range (in the following also referred to as “redlight”). The peak wavelength of the illumination source may be greaterthan 500 nm, greater than 600 nm, or greater than 630 nm. The peakwavelength may be less than 700 nm. The peak wavelength may be 635 nm.Red light has the advantage that it can reach regions in the body whichare further away from the skin with a high intensity more easily thanlight of a shorter wavelength, which is subject to a more pronouncedabsorption than red light in the body tissue. Accordingly, the presentdisclosure uses red light as an example.

In an embodiment the illumination system may be configured to irradiatethe target surface with a predetermined light dose during theillumination session. The light dose may be greater than or equal to oneof the following values when the target surface is arranged at thetarget location relative to the illumination source during theillumination session: 30 J/cm², 35 J/cm², 37 J/cm². Alternatively oradditionally, the light dose may be less than or equal to one of thefollowing values when the target surface is arranged at the targetlocation relative to the illumination source during the illuminationsession: 45 J/cm², 40 J/cm², 37 J/cm². The values above particularlyhold at least for red light.

A sufficient light dose is one of the key requirements to successfullycarry out PDT. However, when choosing the light dose, the maximumtolerable level of pain for the patient must also be taken into account.The range between a light dose of 30 and 45 J/cm², in particular a lightdose of 37 J/cm², may be considered the best compromise between adequatetreatment efficiency and pain burden, e.g. when using red light.

In another embodiment the electromagnetic radiation has a peakwavelength in the blue spectral range (in the following also referred toas “blue light”). The peak wavelength of the illumination source may bebetween 400 nm and 490 nm, e.g. 420 nm.

In an embodiment the illumination system may be configured to irradiatethe target surface with a predetermined light dose during theillumination session. The light dose may be greater than or equal to oneof the following values when the target surface is arranged at thetarget location relative to the illumination source during theillumination session: 8 J/cm², 9 J/cm², 10 J/cm². Alternatively oradditionally, the light dose may be less than or equal to one of thefollowing values when the target surface is arranged at the targetlocation relative to the illumination source during the illuminationsession: 12 J/cm², 11 J/cm², 10 J/cm². The values above particularlyhold at least for blue light.

The range between a light dose of 8 and 12 J/cm², in particular a lightdose of 10 J/cm², may be considered the best compromise between adequatetreatment efficiency and pain burden, e.g. when using blue light.

It should be noted that yellow or green light could also be used. Thisis particularly true if ALA is used as prodrug as the photosensitizerPpIX does not only absorb red and/or blue light, but also green and/oryellow light.

In an embodiment the first mode time interval, the second mode timeinterval, and/or the third mode time interval may be greater than orequal to one of the following values: 1 min, 1.5 min, 2 min, 2.5 min, 3min, 3.5 min, 4 min, 4.5 min, 5 min. Alternatively or additionally, thefirst mode time interval, the second mode time interval, and/or thethird mode time interval may be less than or equal to one of thefollowing values: 10 min, 9.5 min, 9 min, 8.5 min, 8 min, 7.5 min, 7min, 6.5 min, 6 min, 5.5 min, 5 min.

In an embodiment the first mode time interval and/or the second modetime interval may be shorter than the third mode time interval. Thus,the third mode may provide the greatest contribution to the total lightdose delivered to the target surface during the illumination session.

In an embodiment, the priming mode time interval may be shorter than thefirst mode time interval, the second mode time interval and/or the thirdmode time interval.

In an embodiment the priming mode time interval may be less than orequal to one of the following values: 4 min, 3 min, 2 min, 1 min.Alternatively or additionally, the priming mode time interval may begreater than or equal to one of the following values: 10 s, 20 s, 30 s,1 min.

In an embodiment the first mode time interval may be shorter than thesecond mode time interval. In this way, the illumination duration withan intensity less than T may be kept comparatively small. Thus, thesession duration is not unnecessarily extended.

In an embodiment the first mode time interval and/or the second modetime interval may be longer than the duration of a single darker phaseand/or a single illumination phase, preferably at least 5 d, 6 d, 7 d, 8d, 9 d, 10 d, 11 d, 12 d, 13 d, 14 d, 15 d, where d is the duration ofone single darker phase and/or of one single illumination phase.

In an embodiment the duration of one darker phase and/or of oneillumination phase may be less than or equal to one of the followingvalues: 60 s, 50 s, 45 s, 40 s, 35 s, 30 s, 25 s, 20 s. Alternatively oradditionally, the duration of one darker phase and/or of oneillumination phase may be greater than or equal to one of the followingvalues: 15 s, 20 s, 25 s, 30 s. Phase durations in the range between 15and 60 seconds may be advantageous to take advantage of the positiveeffects without increasing the duration of treatment unnecessarily.

In an embodiment the durations of different darker phases in the thirdmode may be equal. In an embodiment the durations of differentillumination phases in the third mode may be equal. In an embodiment thedurations of the darker phases may be constant and may be equal to ordifferent from the duration of the illumination phases.

In an embodiment the duration of the darker phases may be less than theduration of the illumination phases. This results in shorterinterruptions of the illumination during the third mode, which maycontribute to keep the session duration at a desired time.

In an embodiment, the duration of the second mode time interval and/orthe duration of the first mode time interval and the second mode timeinterval when taken together is less than or equal to one of thefollowing values: 12 min, 11 min, 10 min, 9 min, 8 min. Thus, the firstpain relief, e.g. by a darker phase in the third mode after the secondmode, may occur at a time when or before the patient experiences thehighest pain. Patients have been reported to perceive the highest painor unbearable pain after about 10 minutes during PDT sessions, forexample. Therefore, keeping the second mode or the combination of firstand second mode taken together below 10 minutes may be beneficial withrespect to pain management.

In an embodiment the duration of the entire illumination session may beless than or equal to one of the following values: 20 min, 19 min, 18min, 17 min, 16 min, 15 min, 14 min, 13 min. Session durations up to 20minutes are usually accepted by users without problems.

In an embodiment the duration of the entire illumination session may begreater than or equal to one of the following values: 10 min, 11 min, 12min, 13 min. The duration of the session may be between 10 min and 20min, for example.

In an embodiment the intensity during each illumination phase in thethird mode may be the same.

In an embodiment the intensity during the darker phases may be less thanor equal to B or is equal to zero. Therefore, the re-supply with theoxygen may be facilitated in the dark phases.

In an embodiment the intensity in a single illumination phase may beconstant or substantially constant. A constant or substantially constantintensity in a single illumination phase contributes to a morepredictable photodynamic effect.

In an embodiment the intensity may vary between different illuminationphases. Variation of different intensities may be helpful to adjust thepatient's pain burden or load even more during treatment. For example,at the beginning of the third mode, the intensity in the illuminationphase may be higher than near the end of the third mode.

In an embodiment the illumination protocol may govern the entireillumination session.

Another aspect of the present disclosure relates to a method foroperating an illumination source, wherein the illumination source isoperated according to an illumination protocol, e.g. during anillumination session performed with the above described illuminationsystem, and wherein the illumination protocol comprises instructions tooperate the illumination source during the illumination session in theabove described different modes.

In addition, the disclosure also relates to a computer program product,such as a data carrier, e.g. a non-transitory data carrier, or datastream, the computer program product containing machine readableinstructions which, in particular when loaded in and/or executed by acomputer system, e.g. by an electronic control unit thereof, cause anillumination source to operate according to the above mentionedprotocol.

Moreover, another aspect relates to a kit for treating a disease, e.g. askin disease, such as a neoplastic skin disease. The kit may comprise apharmaceutical substance suitable to be topically applied to the skin ina region to be treated and an illumination system as mentioned above,wherein the illumination system is configured to irradiate a region ofthe skin to which the substance has been applied.

In an embodiment the pharmaceutical substance may be a photosensitizingdrug or precursor to such a drug that is excitable by light in theemitted spectrum.

In an embodiment the pharmaceutical substance may comprise5-aminolevulinic acid. 5-aminolevulinic acid has been well studied andis considered a reliable prodrug for generating a photosensitizer.

Yet another aspect relates to a method for treating a skin diseasecomprising the following steps: applying a pharmaceutical substance tothe surface of the skin in a region which is to be treated; irradiatingthe region with an illumination source according to the method asspecified above and/or using the illumination system as specified above.

In an embodiment the illumination system, the kit and/or the method maybe used to treat a skin disease or disorder. The skin disease ordisorder may be or may comprise a neoplastic skin disease, like actinickeratosis, basal cell carcinoma, squamous cell carcinoma in situ, warts,acne, wound healing disorders/chronic wounds, bacterial and/or fungalinfections or inflammatory skin diseases.

It should be noted that the present disclosure covers non-therapeuticmethods.

Due to the low pain burden, the illumination system can be useduniversally for the treatment of various diseases.

Of course, features described above in connection with different aspectsand embodiments may be combined with each other and with featuresdescribed below. Thus, features relating to the system do also apply forthe methods and the kit and vice versa.

Further features and refinements become apparent from the followingdescription of the exemplary embodiments in connection with theaccompanying figures.

FIG. 1 schematically shows a perspective view of an illumination systemand a target surface.

FIG. 2 shows a diagram illustrating an illumination protocol.

FIG. 3 shows a diagram illustrating a variation of the illuminationprotocol of FIG. 2.

FIG. 4 shows a diagram illustrating yet another variation of theillumination protocol of FIG. 2.

FIG. 1 shows an illumination system 1, e.g. for photodynamic therapy(PDT). The illumination system 1 comprises an illumination source 2,which is configured to emit an electromagnetic radiation 3 to illuminatea target surface 4 during operation, and an electric control unit 5. Thetarget surface 4 may be a human skin, for example the skin on a head oranother region to be treated. Furthermore, a PDT requires aphotosensitizer and molecular oxygen (not explicitly shown). Usually thephotosensitizer is obtained by a prodrug (not explicitly shown) which istopically applied to the skin, expediently in the target region, andwhich is then converted by the cells, preferably by neoplastic cells,into the actual photosensitizer. The prodrug may be 5-aminolevulinicacid (5-ALA), an endogenous precursor for heme biosynthesis.

The molecular mechanism of action in PDT is based on cellularaminolevulinic acid uptake, synthesis, and accumulation of thephotosensitizer, which is excited by light of specific wavelengthsleading to the formation of reactive oxygen species (ROS), upon thepresence of oxygen. These ROS species can initiate cell death in theform of apoptosis, necrosis and/or autophagy.

The illumination source 2 is configured such that the intensity of theelectromagnetic radiation 3 emitted by the illumination source 2 and/orthe one reaching the target surface 4 can be varied. Moreover, it ispossible that the distance between the target surface 4 and theillumination source 2 of the illumination system 1 is adjustable andthus variable. It is, however, preferred, that the target surface 4 hasa fixed position relative to the illumination source.

The illumination source 2 may comprise a light-emitting diode (LED) or aplurality of light-emitting diodes. In particular illumination sourcessuch as the ones distributed by the company Biofrontera AG under thetradename BF-RhodoLED® are suitable. The light emitted by thelight-emitting diodes promotes the formation of reactive oxygen species(ROS). The wavelength of the light emitted by the illumination sourcemay be greater than 400 nm, greater than 500 nm or greater than 600 nm.For example, the wavelength may be 635 nm, i.e. radiation in the redspectral range. As another example, the wavelength may be 420 nm, i.e.radiation in the blue spectral range. Alternatively, yellow or greenradiation may also be applicable to activate the photosensitizerappropriately.

The illumination system 1 may have a target location or may define atarget location in which the target surface 2 is to be arranged relativeto the illumination source 2 during the illumination session. The targetlocation may be defined by a bearing surface which is contacted by asection of the user's head, e.g. by the forehead or the chin. Thesection may stay in contact with the bearing surface during the entiresession. The target location may be arranged at a distance from aradiation exit surface of the illumination source 2. A gaseous mediummay be present between the radiation exit surface of the illuminationsource 2, e.g. a surface of an optical element, e.g. a diffusor or alens, and the target surface 4 and/or the target location.

The distance between the radiation exit surface of the illuminationsource 2 and the target location may be less than or equal to one of thefollowing values: 20 cm, 15 cm 10 cm, 8 cm, 7 cm, 6 cm, 5 cm.Alternatively or additionally, the distance between the radiation exitsurface of the illumination source 2 and the target location may begreater than or equal to one of the following values: 1 cm, 2 cm, 3 cm,4 cm, 5 cm. The distance between the radiation exit surface of theillumination source 2 and the target location may be between 1 cm and 20cm, preferably between 5 cm and 8 cm.

The illumination source 2 may comprise at least one optoelectronicsemiconductor chip for generating the electromagnetic radiation, e.g. alight-emitting diode chip. The radiation emitted by the illuminationsource 2 may be incoherent radiation. It may be monochromatic, e.g. oflight of one specific color. The electromagnetic spectrum emitted by theillumination source 2 may have a peak wavelength in the visible spectralrange, e.g. in the red or blue spectral range. The emission spectrum maybe narrow. For example, the full width at half maximum of the spectrum(FWHM: Full Width Half Maximum) may be less than 100 nm, e.g. less thanor equal to 50 nm.

The electronic control unit 5 is operatively connected to theillumination source 2 and configured to control operation of theillumination source 2 according to an illumination protocol during anillumination session performed with the illumination system 1. Theelectronic control unit may be part of a computer. The electroniccontrol unit may be a CPU (Central Processing Unit) or amicrocontroller. The illumination protocol comprises instructions tooperate the illumination source 2 during the illumination session in aplurality of different modes, which are disclosed in detail in FIG. 2.

FIG. 2 shows a diagram of the illumination protocol with two axes, afirst axis representing the duration of the radiation treatment inseconds, and a second axis representing the degree of light intensity inpercent. The illumination protocol may govern the entire illuminationsession.

During a first mode a, which is executed first when using theillumination system 1, the electronic control unit 5 controls operationof the illumination source 2 such that the intensity of theelectromagnetic radiation 3 emitted by the illumination source 2 isincreased continuously or quasi-continuously from a base intensity B(30%) to a target intensity T (100%) within a first mode time interval.

As illustrated in FIG. 2 a linear ramp is applied which increases thelight intensity from 30% to 100% light intensity in the course of 5 or5.5 minutes. Other durations are possible as well, of course. Theintensity at 100% need not be the maximum intensity emittable by theillumination source 2 but rather designates the maximum intensity duringthe illumination session. Alternatively, the intensity may be increasednon-linearly in the first mode a (see FIG. 3, for example). Here, it ispreferred that initially the slope is less than later on, which may beadvantageous to sensitize the nerve endings.

The first mode a enables provision of a moderate reaction onset toreduce initial photobleaching and promote re-oxygenation of the treatedtissue and a slow but continuous increase of the irradiance to trigger asufficient photodynamic effect, including initial inflammatory reactionsthat induce vasodilation for even better oxygen supply. The photodynamiceffect describes the process during PDT which leads to the destructionof cells, wherein photobleaching describes the effect that thephotosensitizer is inactivated by permanent disruption of its chemicalstructure, e.g. by cleavage of covalent bonds. The photobleaching effectmay coincide with temporal oxygen depletion in the target tissue due toa massive initial reaction. This leads to a rapid decrease in oxygen andtherefore limits the formation of ROS. In addition, the milderinitiation phase allows adaptation of sensory nerve endings in the skinto the stimulus, whereby the perceived pain by the patient is reduced.

After reaching 100% light intensity, a second mode b follows, whereinthe electronic control unit 5 controls operation of the illuminationsource 2 such that the intensity of the electromagnetic radiation 3emitted by the illumination source is constant or substantially constantfor a second mode time interval. As shown in FIG. 2, in the second modeb, the maximum light intensity of the first mode a is maintained. Thelight intensity may be kept constant for approximately 4.5 minutes.Other durations are possible as well, of course.

This second mode b is important to provide high energy to the target ina relatively short time span and thus keeps the overall duration of thesession well below 16 minutes, which is considered acceptable by mostpatients and physicians regarding the pain burden. Apart from that, theelectronic control unit 5 controls the operation of the illuminationsource 2 such that the illumination source 2 is operated so that theirradiance is stopped or the intensity is reduced after 10 minutes, e.g.by the first darker phase in a subsequent mode (mode c which isdiscussed below), thereby counteracting an excessive increase in pain.

In the second mode b the intensity of the electromagnetic radiationemitted by the illumination source is constant or substantiallyconstant. The intensity during the second mode b may be equal to thetarget intensity T in the first mode.

Then the second mode b is followed by a third mode c. The third mode cis the last mode of the protocol. In the third mode c, the electroniccontrol unit 5 controls operation of the illumination source 2 such thatthe illumination source 2 is operated such that darker phases andillumination phases alternate for a third mode time interval, e.g. for 6minutes. The duration of the third mode may be adjusted such that adesired light dose is received at the target surface e.g. 37 J/cm²,which is particularly suitable at least for red light, or 10 J/cm²,which is particularly suitable at least for blue light.

The intensity of the electromagnetic radiation 3 emitted by theillumination source 2 is lower in the darker phases than in theillumination phases. In the example shown, the illumination source 2does not emit electromagnetic radiation in the darker phases, whereasthe illumination source 2 emits electromagnetic radiation 3 in theillumination phases, wherein the light intensity of the illuminationphases is identical to the light intensity of mode 2 and the maximumlight intensity of mode 1. Of course, the relative intensities may beadjusted as required.

This alternating intensity may be maintained for approximately 4 minutesor more in the third mode c. In the example shown in FIG. 3, theprotocol contains seven illumination phases and seven dark phases, whichin particular allows for the neuronal activation to wear off to someextent to reduce pain. The duration in the third mode c of one of thedarker phases is constant and is equal to the duration of one of theillumination phases. The duration of a phase is 20 seconds each. Duringthe illumination phases the light intensity is kept at 100%. Afterapproximately 14 minutes the illumination is stopped completely and thethird mode c is ended. The number of illumination phases and darkerphases may vary, of course, as may the absolute or relative duration.Also, instead of not operating the light source to emit no radiation atall during the darker phases, a low intensity, e.g. up to 30% of themaximum intensity may still be tolerable. The intensity in a singleillumination phase may be constant or substantially constant.

Due to the alternating phases the target tissue may be provided withenough dark phases to reduce photobleaching and/or to promotere-oxygenation of the treated tissue, which may lead to an increase inefficacy. In addition, the paused illuminations of the last mode c allowfor the neuronal activation to wear off to some extent. Therefore theperceived pain is significantly reduced.

This third mode c extends until a total light dose of approximately 37J/cm² may be reached. An increased protocol duration while maintaining alight dose of approximately 37 J/cm² is beneficial, as it is likely toensure a most balanced rate of oxygen consumption and resupply. Thevalue of 37 J/cm² particularly holds at least for red light. Anincreased protocol duration while maintaining a light dose ofapproximately 37 J/cm² is beneficial, as it is likely to ensure a mostbalanced rate of oxygen consumption and resupply.

Alternatively, the third mode c extends until a total light dose ofapproximately 10 J/cm² may be reached. The value of 10 J/cm²particularly holds at least for blue light. An increased protocolduration while maintaining a light dose of approximately 10 J/cm² isbeneficial, as it is likely to ensure a most balanced rate of oxygenconsumption and resupply.

If yellow or green light is used, the targeted total light dose may beadjusted appropriately.

The duration of the entire illumination session is expediently keptbelow 20 minutes or even 16 minutes.

The fractionation of the illumination by dark intervals alternating withhigher intensity light, allows re-oxygenation and thus additionalphotosensitizer activation, especially in the later phases of theillumination when high fluence rates are used, in order to prevent lateoxygen depletion. Consequently, the limited treatment time due to paincan be used in a time-efficient manner.

The durations of different darker phases in the third mode c may beequal and/or constant as depicted as may be the durations of differentillumination phases in the third mode c. Alternatively, the durationsmay vary between different darker phases and/or different illuminationphases. The same holds for the intensity in the illumination phases,which may be varied, e.g. reduced towards the end of the illuminationsession. In an embodiment, the duration of the darker phases may be lessthan the duration of the illumination phases. This results in shorterinterruptions of the illumination during the third mode, which maycontribute to keep the session duration at a desired time.

The beginning of the operation of the illumination source 2 in the firstmode a may define the start of the illumination session and the end ofthe operation of the illumination source 2 in the third mode c maydefine the end of the illumination session.

FIG. 3 illustrates a variation of the illumination protocol shown inFIG. 2. Here, in the first mode of operation (mode a), initially, theintensity is increased non-linearly at a slower rate than later on. Ininterval a1, the increase may be non-linear, whereas in the subsequentinterval a2 it may be linear. The (constant) slope in the linear sectionmay be greater than or equal to every slope in the non-linear section.From mode b, the protocol may be continued as depicted in FIG. 2, forexample.

FIG. 4 illustrates another variation of the illumination protocol shownin FIG. 2. Here, a priming mode p is included before mode a iscommenced. The duration of the priming mode may be 3 min or less. Theintensity P during the priming mode may be equal to the intensity Bdiscussed in FIG. 2. In the embodiments in FIGS. 3 and 4, the onset ofthe second mode (mode b) is merely as an example shown to be at about340 s.

The duration of the entire illumination session may be less than orequal to one of the following values: 20 min, 19 min, 18 min, 17 min, 16min, 15 min, 14 min, 13 min.

The first mode time interval and/or the second mode time interval may beshorter than the third mode time interval. The first mode time intervalmay be shorter than the second mode time interval or longer.

Above, some durations have been specified for the modes. However, therespective mode—first mode, second mode and/or third mode—may be appliedfor a time interval which is greater than or equal to one of thefollowing values: 1 min, 1.5 min, 2 min, 2.5 min, 3 min, 3.5 min, 4 min,4.5 min, 5 min. Alternatively or additionally, the respective mode maybe applied for a time interval which is than or equal to one of thefollowing values: 10 min, 9.5 min, 9 min, 8.5 min, 8 min, 7.5 min, 7min, 6.5 min, 6 min, 5.5 min, 5 min. In this way, the illuminationprotocol may be adjusted to different situations, for example.

The present disclosure also provides a computer program product, such asa data carrier, e.g. a non-transitory data carrier, or data stream, maycontain machine readable instructions which, in particular when loadedin and/or executed by a computer system, e.g. by the electronic controlunit 5 thereof, cause the illumination source 2 to be operate accordingto the above-mentioned protocol.

The illumination system 1 may be used to treat a skin disease ordisorder. The skin disease or disorder may be or may comprise aneoplastic skin disease, like actinic keratosis, basal cell carcinoma,squamous cell carcinoma in situ, or warts, acne, wound healingdisorders/chronic wounds, bacterial and/or fungal infections orinflammatory skin diseases. However, it should be noted that it may alsobe used for non-therapeutic methods.

A kit for treating a disease, e.g. a skin disease, such as a neoplasticskin disease may comprise a pharmaceutical substance suitable to betopically applied to the skin in a region to be treated and theillumination system 1 as mentioned above, wherein the illuminationsystem 1 is configured to irradiate a region of the skin to which thesubstance has been applied. The pharmaceutical substance may be aphotosensitizing drug or precursor to such a drug that is excitable bylight in the emitted spectrum.

A method for treating a skin disease, e.g. one of the ones mentionedfurther above may comprise the following steps: applying apharmaceutical substance, e.g. the prodrug mentioned above, to thesurface of the skin in a region which is to be treated; irradiating theregion, e.g. with the illumination source 2 according to the method asspecified above and/or using the illumination system 1 as specifiedabove.

While applying the illumination protocols as discussed above it is notonly expected to increase the efficacy but also to reduce thesignificance of the pain sensation for the patient/user or the painperceived overall. A substantial amount of perceived pain is one of themajor issues that hinders broad acceptance of PDT by patients. Usuallypatients report to experience a relatively high amount of pain duringthe illumination which ranges from mild inconvenience to severe pain upto a point where the treatment has to be aborted. This, of course, hasgreat negative implication for an individual PDT session and PDTtreatment as a whole.

The application of the proposed illumination system for photodynamictherapy reduces pain during PDT to a well tolerable level. In additionto this, the acceptance of the treatment itself and the willingness toundergo PDT again is greatly improved when employing this illuminationsystem.

Although PDT is a highly effective treatment method, reoccurrence of thetreated disease, e.g. actinic keratosis or another one of the diseasesmentioned earlier in this disclosure, is common and thus patients often,although being successfully treated, later develop different lesion atdifferent skin areas and again require medical intervention. Moreover,some patients are not completely cleared after a single PDT session andrequire a second session. If the first PDT they received was verypainful, the completion of a second PDT is highly unlikely despite thefact that it offers supreme efficacy compared to other therapy options.

Consequently, the proposed illumination system and protocol increase theacceptance levels for photodynamic therapy.

One particular illumination system and/or its associated protocol hasbeen described above. However, it should be appreciated that differentsystems and protocols can be applied as well, especially using featureswhich have been discussed in the introductory section of thisdisclosure, even if these features are not explicitly described above inconjunction with the figures. Thus, the features discussed in theintroductory section are made subject to the exemplary embodiments ofthis disclosure by explicit reference to these features.

REFERENCE NUMERALS

-   1 illumination system-   2 illumination source-   3 electromagnetic radiation-   4 target surface-   5 electronic control unit-   p priming mode-   a first mode-   b second mode-   c third mode

What is claimed is:
 1. An illumination system for photodynamic therapy,the illumination system comprising an illumination source, which isconfigured to emit an electromagnetic radiation to illuminate a targetsurface during operation, and an electronic control unit, wherein theillumination source is configured such that the intensity of theelectromagnetic radiation emitted by the illumination source can bevaried, wherein the electronic control unit is operatively connected tothe illumination source and configured to control operation of theillumination source according to an illumination protocol during anillumination session performed with the illumination system, and whereinthe illumination protocol comprises instructions to operate theillumination source during the illumination session in a plurality ofdifferent modes, the modes comprising: a) a first mode, wherein, in thefirst mode, the electronic control unit controls operation of theillumination source such that the intensity of the electromagneticradiation emitted by the illumination source is increased continuouslyor quasi-continuously from a base intensity B to a target intensity Twithin a first mode time interval, b) a second mode, wherein, in thesecond mode, the electronic control unit controls operation of theillumination source such that the intensity of the electromagneticradiation emitted by the illumination source is constant orsubstantially constant for a second mode time interval, and c) a thirdmode, wherein, in the third mode, the electronic control unit controlsoperation of the illumination source such that the illumination sourceis operated such that darker phases and illumination phases alternatefor a third mode time interval, wherein the intensity of theelectromagnetic radiation emitted by the illumination source is lower inthe darker phases than in the illumination phases, or wherein, in thedarker phases the illumination source does not emit electromagneticradiation whereas the illumination source emits electromagneticradiation in the illumination phases.
 2. The illumination system ofclaim 1, wherein B is less than or equal to one of the following values:0.5 T, 0.45 T, 0.4 T, 0.35 T, 0.3 T.
 3. The illumination system of claim1, wherein B is greater than or equal to one of the following values:0.1 T, 0.15 T, 0.2 T, 0.25 T, 0.3 T.
 4. The illumination system of claim1, wherein the illumination source is operated in the second mode afterthe first mode and/or before the third mode during the illuminationsession.
 5. The illumination system of claim 1, wherein the beginning ofthe operation of the illumination source in the first mode defines thestart of the illumination session and the end of the operation of theillumination source in the third mode defines the end of theillumination session.
 6. The illumination system of claim 1, whereinevery mode selected from the first mode, the second mode, and the thirdmode of operation of the illumination source occurs once, preferablyonly once, during the illumination session.
 7. The illumination systemof claim 1, wherein the electromagnetic radiation has a peak wavelengthin the visible spectral range, e.g. in the red, green, yellow, or bluespectral range.
 8. The illumination system of claim 1, wherein thetarget surface is arranged at a target location relative to theillumination source during the illumination session, and wherein theillumination system is configured to irradiate the target surface with apredetermined radiation dose during the illumination session.
 9. Theillumination system of claim 8, wherein the radiation dose is greaterthan or equal to one of the following values when the target surface isarranged at the target location relative to the illumination sourceduring the illumination session: 30 J/cm2, 35 J/cm2, 37 J/cm2.
 10. Theillumination system of claim 8, wherein the radiation dose is less thanor equal to one of the following values when the target surface isarranged at the target location relative to the illumination sourceduring the illumination session: 45 J/cm2, 40 J/cm2, 37 J/cm2.
 11. Theillumination system of claim 8, wherein the radiation dose is greaterthan or equal to one of the following values when the target surface isarranged at the target location relative to the illumination sourceduring the illumination session: 8 J/cm2, 9 J/cm2, 10 J/cm2.
 12. Theillumination system of claim 8, wherein the radiation dose is less thanor equal to one of the following values when the target surface isarranged at the target location relative to the illumination sourceduring the illumination session: 12 J/cm2, 11 J/cm2, 10 J/cm2.
 13. Theillumination system of claim 8, wherein the distance between theradiation exit surface of the illumination source and the targetlocation is between 1 cm and 20 cm, preferably between 5 cm and 8 cm.14. The illumination system of claim 1, wherein the duration of theentire illumination session is less than or equal to one of thefollowing values: 20 min, 19 min, 18 min, 17 min, 16 min, 15 min, 14min, 13 min.
 15. A method for operating an illumination source, whereinthe illumination source is operated according to an illuminationprotocol during an illumination session performed with the illuminationsystem, and wherein the illumination protocol comprises instructions tooperate the illumination source during the illumination session in aplurality of different modes, the modes comprising: a) a first mode,wherein, in the first mode, the illumination source is operated suchthat the intensity of the electromagnetic radiation emitted by theillumination source is increased continuously or quasi-continuously froma base intensity B to a target intensity T within a first mode timeinterval, b) a second mode, wherein, in the second mode, theillumination source is operated such that the intensity of theelectromagnetic radiation emitted by the illumination source is constantor substantially constant for a second mode time interval, and c) athird mode, wherein, in the third mode, the illumination source isoperated such that darker phases and illumination phases alternate for athird mode time interval, wherein the intensity of the electromagneticradiation emitted by the illumination source is lower in the darkerphases than in the illumination phases, or wherein, in the darker phasesthe illumination source does not emit electromagnetic radiation whereasthe illumination source emits electromagnetic radiation in theillumination phases.
 16. A computer program product, such as a datacarrier, e.g. a non-transitory data carrier, or data stream, thecomputer program product containing machine readable instructions which,in particular when loaded in and/or executed by a computer system, e.g.by an electronic control unit thereof, cause an illumination source tobe operated according to the method of claim
 15. 17. A kit for treatinga disease, in particular a skin disease, comprising: a pharmaceuticalsubstance suitable to be topically applied to the skin in a region to betreated, and an illumination system as claimed in claim 1, wherein theillumination system is configured to irradiate a region of the skin towhich the substance has been applied.
 18. A method for treating a skindisease comprising the following steps: a) applying a pharmaceuticalsubstance to the surface of the skin in a region which is to be treated;b) irradiating the region with an illumination source according to themethod as specified in claim 15 and/or using the illumination system ofclaim
 1. 19. The method of claim 18, wherein the pharmaceuticalsubstance is a photosensitizing drug or precursor to such a drug that isexcitable by radiation in the emitted spectrum.
 20. The method of claim18, wherein the skin disease is a neoplastic skin disease like actinickeratosis, basal cell carcinoma, squamous cell carcinoma in situ, orwarts, acne, wound healing disorders/chronic wounds, bacterial and/orfungal infections, inflammatory skin diseases.
 21. The illuminationsystem of claim 1, wherein the first mode time interval, the second modetime interval, and/or the third mode time interval is greater than orequal to one of the following values: 1 min, 1.5 min, 2 min, 2.5 min, 3min, 3.5 min, 4 min, 4.5 min, 5 min.
 22. The illumination system ofclaim 1, wherein the duration of one darker phase and/or of oneillumination phase is greater than or equal to one of the followingvalues: 15 s, 20 s, 25 s, 30 s.